Extreme Fluctuations in Wnt/beta-Catenin Signaling as an Approach for Colon Cancer Prevention and Therapy

Mutations in the Wnt/beta-catenin (Wnt) signaling pathway initiate most cases of sporadic colon cancers (CC); therefore one approach for CC prevention and therapy is to suppress Wnt activity. However, the prolonged suppression of the signaling pathway is detrimental to the intestinal stem cells that rely on Wnt signaling for survival. Furthermore, CC cells exposed for an extended period of time to a single Wnt signaling modulating agent may develop resistance to it. A possible solution is suggested by our findings that: (a) butyrate, a colonic metabolite of dietary fiber, and synthetic histone deacetylase inhibitors that mimic the effects of butyrate, hyperactivate Wnt transcriptional activity in CC cells with mutations in the pathway, and (b) high fold changes of Wnt signaling induce high apoptotic levels in the mutated cells. Therefore, dietand drug-based regimens that result in alternating periods of suppressed and hyper-activated Wnt signalling may become powerful anti-CC preventive and therapeutic approaches. The hypothesis can be tested by (1) evaluating the effects of drugand dietbased regimens, which induce maximal fluctuations in Wnt signaling, on the adenoma burden of Apc/min mice, an established in vivo model of intestinal cancer, (2) epidemiological studies analyzing the dietary habits, such as daily fasting hours and fiber intake, of healthy individuals and patients with positive colonoscopies, and 352 D. L. Lazarova and M. Bordonaro (3) examining the ability of different diets to produce colonic lumen content with apoptotic and Wnt-modulatory functions.